Clinical Information

This consultative study is primarily designed for the evaluation of microcytosis but also has the ability to test for the detection of almost all known hemoglobin disorders in an economical manner. Because this can include multiple tests for alpha thalassemias, beta thalassemias, delta-beta thalassemia, hereditary persistence of fetal hemoglobin (HPFH), and for all known hemoglobin (Hb) variants, an expert in these disorders can guide testing to explain the clinical question or reported complete blood cell count values. This evaluation is particularly useful for complete classification of compound combinations of Hb S with alpha or beta thalassemia, Hb E/beta-0-thalassemia, and many other complex alpha and beta thalassemia disorders. Since iron deficiency can mimic thalassemias, ferritin levels are measured to evaluate this possibility if a serum sample is received.

Hb disorders include those associated with thalassemias (decreased protein quantity) and Hb variants (abnormal protein production). Many are clinically harmless, and others cause symptoms, including microcytosis, sickling disorders, hemolysis, erythrocytosis, cyanosis/hypoxia, long-standing or familial anemia, compensated or episodic anemia, and increased methemoglobin or sulfhemoglobin results. Hb disorders can show patterns of either autosomal recessive or autosomal dominant inheritance.

The thalassemias are a group of disorders of Hb synthesis. Normal adult Hb consists of 2 alpha-globin chains (encoded by 2 pairs of alpha-globin genes, each pair located on chromosome 16), and 2 beta-globin chains (encoded by 2 beta-globin genes, each located on chromosome 11). Thalassemia syndromes result from an underproduction of 1 or 2 types of globin chains and are characterized by the type (alpha, beta, delta, gamma) and magnitude of underproduction (number of defective genes) and the severity of clinical symptoms (minor, intermedia, major). The severity of the clinical and hematologic effects is directly related to the imbalance of alpha-like to beta-like chains.

The most common form of thalassemia is alpha thalassemia. Alpha thalassemia usually involves deletion of entire alpha genes and varies in severity depending on the number of alpha chains deleted (or rendered nonfunctional). Alpha thalassemia trait usually results from the deletion of 2 alpha genes. The most common form of Hb H disease, results from dysfunction of 3 alpha chains, and shows a variable phenotype with most showing moderate anemia. The deletion of all 4 alpha genes (Barts hydrops fetalis) is incompatible with life without significant medical intervention. Nondeletional alpha thalassemia alterations can also result in either thalassemia trait or Hb H disease and are less common than deletional forms.

Conversely, most beta thalassemia alterations are due to single nucleotide substitutions that can occur anywhere in the beta-globin gene. Large deletions of the beta-globin gene complex can result in elevations in Hb F, such as HPFH or delta-beta thalassemia. While the presence of a single beta-gene variants (beta thalassemia trait) results primarily in red blood cells microcytosis, cases with 2 beta-gene abnormalities show a wide range in clinical severity, and many cases require molecular testing to understand the phenotype.